Synthesis of allylamines in enantiomerically pure form

Article abstract of DOI:10.1016/S0040-4039(00)00623-7

Enantiopure allylamines are obtained without racemization by reaction of α-amino aldehydes with chloromethyllithium followed by lithiation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00623-7

Tetrahedron Letters 41 (2000) 4361±4362
Synthesis of allylamines in enantiomerically pure form
Jose M. Concellon,* Beatriz Baragana and Estela Riego
Â
Departamento de Quõmica Organica e Inorganica, Facultad de Quõmica, Universidad de Oviedo, Julian Claverõa,
Â
Â
Â
Â
8, 33071 Oviedo, Spain
Â
Received 11 February 2000; accepted 7 April 2000
Abstract
Enantiopure allylamines are obtained without racemization by reaction of a-amino aldehydes with
chloromethyllithium followed by lithiation. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amines; elimination reactions; enantiomeric purity; lithiation.
Chiral allylamines are synthetic precursors to a number of important classes of compounds,
such as 4-aminoallylsilanes,1 aminoepoxides,2 iodocyclocarbamates3 and isoxazolines.4 One
general method3 for the synthesis of allylic amines involves the Wittig ole®nation reaction with
amino aldehydes.5 However, a-amino aldehydes are often susceptible to racemization6 and there
is a possibility that racemization may also occur during the Wittig reaction.2a
Previously, we have reported the synthesis of chiral erythro or threo aminoepoxides by epoxidation
of erythro or threo 3-amino-1-haloalkan-2-ols. These enantiopure halohydrins can be obtained by
reaction of halomethyllithium (generated in situ) with a-amino aldehydes or by reduction of chiral
a0-amino a-chloro ketones, respectively.7 Herein we wish to report a general one-pot synthesis of
enantiopure allylamines by lithiation of chiral 3-amino-1-haloalkan-2-ols, which can be prepared
by reaction of chloromethyllithium with chiral a-amino aldehydes.
The reaction of amino aldehyde 1 with chloromethyllithium (generated in situ from chloro-
iodomethane and methyllithium) at ^78ꢀC led to the expected chlorinated lithium alcoholate 2;
this intermediate was in situ lithiated with lithium powder at ^45ꢀC a€ording a b-functionalized
organolithium intermediate 3, which undergoes spontaneous b-elimination yielding, after hydrolysis,
the corresponding allylamine 4 (Scheme 1).
Under these reaction conditions, the allylic amines 4 were obtained with no detectable racemi-
zation. The enantiomeric purity of product 4b was determined by chiral HPLC (Chiracel OD-H)
analysis,8 showing an enantiomeric excess (ee) >99%. Previously, other chiral HPLC analysis
was carried out, using a racemic mixture of 4b to exclude the possibility of co-elution of both
enantiomers.
* Corresponding author. Fax: 34-8-510-3446; e-mail: jmcg@sauron.quimica.uniovi.es
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00623-7

4362
Scheme 1. Synthesis of enantiopure allylamines
The described transformation can also be carried out with functionalized amino aldehydes such
as O-silylated serinal 1d and it is noteworthy that this methodology provides directly enantiopure
allylamines, from a-amino aldehydes, without isolating the intermediate 2.
A typical procedure for the synthesis of allylamines 4 is as follows: to a ^78ꢀC solution of the
corresponding aldehyde 1 (3 mmol) and chloroiodomethane (0.436 mL, 6 mmol) in THF (10 mL)
was added methyllithium (4 mL of 1.5 M solution in diethyl ether, 6 mmol) dropwise over 5 min
and under nitrogen. After stirring at ^78ꢀC for 30 min, lithium powder (0.216 g, 30 mmol) was
added at ^45ꢀC, and the mixture was stirred for 8 h at the same temperature. The resulting
mixture was treated with ice and after the usual work-up, crude allylamine 4 was obtained.
Column ¯ash chromatography over silica gel (15:1 hexane:ethyl acetate) provided the corre-
sponding pure allylamine 4.
In conclusion, we have described a direct, easy and simple transformation without racemiza-
tion, of a-amino aldehydes into enantiopure allylamines.
Acknowledgements
We thank II Plan Regional de Investigacion del Principado de Asturias (PBP-PGI98-04) and
Ministerio de Educacion y Cultura (PB97-1278) for ®nancial support. E.R. thanks the Ministerio
de Educacion y Cultura for a predoctoral fellowship.
References
1. Franciotti, M.; Mordini, A.; Taddei, M. Synlett 1992, 137±138.
2. (a) Luly, J. R.; Dellaria, J. F.; Plattner, J. J.; Soderquist, J. L.; Yi, N. J. Org. Chem. 1987, 52, 1487±1492. (b)
Romeo, S.; Rich, D. H. Tetrahedron Lett. 1993, 34, 7187±7190. (c) Albeck, A.; Persky, R. J. Org. Chem. 1994, 59,
653±657. (d) Branat, J.; Kvarnstrom, I.; Classon, B.; Samuelson, B.; Nilroth, U.; Danielson, H.; Karlen, A.;
Halberg A. Tetrahedron Lett. 1997, 38, 3483±3486.
3. Kobayashi, S.; Isobe, T.; Ohno, M. Tetrahedron Lett. 1984, 25, 5079±5082.
4. Nishi, T.; Moreisawa, Y. Heterocycles 1989, 29, 1835±1842.
5. Reetz, M. T. Chem. Rev. 1999, 99, 1121±1162.
6. (a) Fehrentz, J. A.; Castro, B. Synthesis 1983, 676±678. (b) Rettle, K. E.; Hommick, C. F.; Ponticello, G. S.;
Evans, B. E. J. Org. Chem. 1982, 47, 3016±3018. (c) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1988, 110,
7447±7455.
7. (a) Barluenga, J.; Baragana, B.; Alonso, A.; Concellon, J. M. J. Chem. Soc., Chem. Commun. 1994, 969±970. (b)
Barluenga, J.; Baragana, B.; Concellon, J. M. J. Org. Chem. 1995, 60, 6696±6699.
8. UV detector 325 nm, 0.8 mL/min, 400:1 hexane:isopropanol; tR: 6.38 min.